Systemic amyloid diseases such as the transthyretin (TTR) amyloidoses are a class of devastating disorders caused by the pathologic aggregation and deposition of specific destabilized proteins as amyloid fibrils on tissues distal from the site of protein synthesis. Currently, no non-invasive therapies exist to treat the majority of these diseases, making systemic amyloidoses a large unmet medical need. A primary factor defining the pathologic extracellular protein aggregation central to these disorders is the secretion of destabilized, amyloidogenic proteins from effector tissues such as the liver. The efficient secretion of these proteins increases serum concentrations of amyloidogenic protein available for pathologic, concentration-dependent aggregation, directly impacting disease pathogenesis in patients. Clinical results from liver transplant recipients show that reducing serum concentrations of amyloidogenic proteins can decrease pathologic protein aggregation, attenuate peripheral proteotoxicity and improve prognosis for patients presenting with a variety of distinct systemic amyloidoses. We hypothesize that activating the endogenous Unfolded Protein Response (UPR) signaling pathways that regulate protein secretion from effector tissues is a non-invasive strategy to similarly decrease secretion and reduce extracellular concentrations of amyloidogenic proteins available for pathologic extracellular aggregation. Consistent with this prediction, we show that activating the UPR- associated transcription factor ATF6 reduces secretion of destabilized, amyloidogenic TTR mutants, but does not affect the secretion of wild-type TTR or the endogenous secreted proteome. Here, we employ TTR as a model amyloidogenic protein to show that ATF6 activation has therapeutic potential to reduce pathologic extracellular aggregation and proteotoxicity of amyloidogenic TTR mutants using a novel patient-derived, multi- system induced pluripotent stem cell model of TTR amyloid disease that recapitulates nearly all aspects of TTR amyloid disease pathology observed in patients. Furthermore, we are extending this analysis to show that ATF6 activation similarly reduces the secretion and proteotoxicity of amyloidogenic proteins involved in other systemic amyloid diseases including Light Chain Amyloidosis - an acquired systemic amyloid disease that affects >1 million individuals worldwide. Through these efforts, we will show that the stress-independent activation of UPR-associated signaling pathways such as that regulated by ATF6 is a broadly-applicable therapeutic strategy to reduce the secretion and pathologic extracellular aggregation of amyloidogenic proteins associated with multiple systemic amyloid diseases. These results will further motivate our ongoing high- throughput screening efforts to identify ATF6 activators, as a single small molecule ATF6 activator has the potential to treat multiple systemic amyloidoses (i.e. a one-drug:multiple-disease therapeutic paradigm) dramatically improving the economics of translating selective ATF6 activators into the clinic to ameliorate pathologic extracellular aggregation associated with these diseases.